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In May 2009, HTU wrote about cervical cancer in women
with HIV (Cervical cancer and you, HTU 186).1 That article
quoted recommendations for “aggressive” annual screening for cervical cell
changes, because women with HIV were twice as likely to be infected with the
human papillomavirus (HPV), the virus that causes the cancer, three to four
times more likely to develop pre-cancerous abnormal cells, and twelve times more
likely to get invasive cervical cancer if they do.2 If they do get
cancer, there is a one in three chance they will be dead of it within ten
years.3 But a simple procedure under local anaesthetic can remove
pre-cancerous cells if they are identified – and the national screening
programme has cut mortality by nearly two-thirds.4 And we now have a
vaccine against the two most common cancer-causing varieties of HPV, with a
programme to give that vaccine to all teenage girls.

Anal cancer
is caused by the same virus and, in the same way as cervical cancer, causes
pre-cancerous changes in cells that can be screened for and treated. It’s about 16 times rarer than cervical
cancer in the general population. But it’s about 60% more common in women than
men and about 50 times more common in gay men with HIV (because anal sex is a
risk factor) – which makes it as common in them as cervical cancer is in
HIV-positive women and is a huge risk increase: for comparison, lung cancer is
‘only’ 25 times more common in heavy smokers than in non-smokers.5
If you do develop anal cancer, there’s a one-in-three chance you’ll die of it
within five years.6,7

But, unlike
the regular check-ups for cervical cancer in women, there is no standard
screening for anal cancer, or even any agreement about whether it would be a
good thing. And although the HPV vaccine has been licensed for use in boys in
the US, a licence for this
use has not been granted in Europe.

Why not?
Should we be agitating for better screening – especially of gay men with HIV –
for anal cancer and for extending the HPV vaccine to boys?

HPV and anal cancer – the facts

Cervical and
anal cancers are caused almost entirely by a viral infection – HPV – which is
not one virus, but a family of about 100 different ones that cause everything
from common warts to genital warts to cancers. The majority of sexually active
adults eventually acquire at least one variety of HPV and it’s a near-universal
infection in people with HIV. For the majority of people HPV has no symptoms.

Only specific
varieties of HPV – the so-called ‘high-risk’ types – cause cancers. HPV 16 is
the most common as an infection and is associated with the highest rate of
progression to cancer. The second most common and aggressive type in the US and Europe
is HPV 18. There are at least twelve other high-risk types, some of which are
more common than type 18 in other parts of the world but tend to be less
aggressive. Types 16 and 18 between them cause 70% of cervical cancers and 80%
of anal cancers worldwide.8

One important
fact about HPV is that, in most cases, the body eventually gets rid of the
infection. The average length of any single anal HPV infection is five months
to a year in HIV-negative people: people with weaker immune systems may take
longer to get rid of it.9

Anal cancer
differs from cervical cancer in that there is less association between CD4
count and risk, although people with lowered immunity are at greater risk of
anal cancer. Most of the increased prevalence is amongst gay men regardless of
HIV status.10 This may be due to more frequent infection with a
greater variety of types of HPV, largely due to anal intercourse. HIV therapy
is not reducing HPV incidence. A recent French study found that 98% of gay men
diagnosed with HIV already had evidence of at least one HPV type, 92% a
high-risk type and 43% HPV 16; after two years on HIV therapy these percentages
were not significantly lower.11

There are now
two HPV vaccines, Merck’s Gardasil and
GlaxoSmithKline’s Cervarix. Both
vaccines protect against infection with HPV types 16 and 18, and Gardasil against the two most common
low-risk genital wart varieties too (HPV 6 and 11).

Testing and grading

The high-risk
HPV types tend not to cause obvious genital warts but do cause changes to the
appearance and function of cells in the anal canal, which can be seen under
medical examination. Areas either lose all pigment and look white, or get
hyperpigmented and look red. While only a tiny proportion of people with HPV
will go on to develop cancer, these changes are very common and can be graded
by severity. Two grading categories are used, according to the type of medical
test done.

In a smear test, some cells from the anal
region are swabbed off with a sample stick. These cells are suspended in fluid,
stained and examined under a microscope, a process called cytology. Cells modified by HPV often have larger or multiple
nuclei, thicker walls and a generally ‘denser’ appearance.

Cells are
graded according to their individual appearance into: normal; ‘atypical
squamous cells of undetermined significance’ (ASCUS); and low- and high-grade ‘squamous intraepithelial lesion’ (LSIL and HSIL). If they are fully-fledged cancer cells, but there is no
invasive cancer, the diagnosis may be adenocarcinoma in situ (AIS).

In an anoscopy,
the physician will visually examine the anal region in more detail using a
proctoscope, and take biopsies: small snips of whole tissue. These will then be
examined under the microscope in a process called histology, which looks at changes in the whole tissue and how it is
organised, rather than at individual cells: for instance, what proportion of
cells in the biopsy have become atypical and whether the lesion just affects
the epithelium – the surface membrane of the anal tissue – or has penetrated to
deeper areas. Any lesions are then graded into anal intraepithelial neoplasia (AIN), grades 1, 2 or 3.

Cytology is sensitive – it is good at picking up signs of
pre-cancerous changes in cells – but HPV specialists at the Chelsea and
Westminster Hospital found that it only correctly predicted the AIN grade in
40% of cases.12 This is in contrast to cervical cytology in
screening, which is over 90% specific.13 So, while a smear test may
be the cheapest and most convenient way of screening for possible anal cancer,
an anoscopy is the only way to decide if changes warrant treatment. For the
types of treatment people can be given, see below.

Screening

Given the comparative rarity of anal cancer, screening
the general public is not considered necessary. But for those at higher risk
(gay men with HIV, possibly all gay men and women who have anal sex), cervical
screening is a good precedent for the value of anal screening. In the UK, cervical
screening is offered to women aged 25 to 65. The death rate due to cervical
cancer in women under 45 went down by nearly two-thirds between 1988, when
screening was introduced, and 2002, despite there being an increase in genital
wart diagnoses at the same time.14

So surely we should be trying to do the same for anal
cancer?

Professor Mark Bower is a consultant at London’s
Chelsea and Westminster Hospital,
specialising in HIV-related cancers. Though in favour of people with HIV having
regular anal screening, he says that the case for it being routine is
surprisingly hard to make.

That’s partly because it’s still relatively rare. In the Chelsea and Westminster
cohort, they have seen 60 cases in 11,112 patients (one per 188 patients)
throughout the clinic’s history, but this includes patients coming to the
hospital specifically to see HPV and anal cancer specialists. In patients
attending the Chelsea and Westminster’s general HIV clinic, they see
fewer than one new case a year.

This may seem odd, given that rates of AIN are very high.
For instance, one study of HIV-positive men found that despite AIN grades 2 or 3 being
found at least once in 133 of the 247 patients in the study (54%), there were
only two cases of anal cancer in three years.15

We don’t know
exactly why some anal (or cervical) lesions turn into an invasive cancer, and
others don’t. Bower has evaluated the cases of nearly 1000 HIV-positive men who
have sex with men seen over the last ten years at the Chelsea
and Westminster.

“These guys’
AIN grade goes up and down and up again,” he says. “A lot of them have been
coming here for ten years and show no signs of progressing.”

This is
partly due to the natural history of HPV and the fact that infections regress
as often as they recur. Most AIN grade 1 lesions simply disappear and only a
minority progress to higher grades. We don’t even know the rate at which
high-grade AIN lesions change into anal cancer: estimates vary hugely from 0.2
to 12.5% a year (the consensus is between 1 and 5%). The thing that keeps
lesions coming back in gay men is not persistent HPV infection but reinfection;
in HIV-positive gay men, persistent infection adds to the risk.

Or incidence
of anal cancer may be lower than expected because, in many patient cohorts, gay
men with HIV are already being screened regularly. Even in cervical cancer, it
has been difficult to calculate the benefit of national screening because so
much ad hoc screening was being done before the national programme began.

“Maybe it’s
because of our excellent interventions,” says Bower, “or maybe it’s because
progression to cancer just doesn’t happen in most people with AIN.” There has
never actually been a randomised controlled trial of cervical cancer screening,
and there couldn’t ethically be one of an HPV-associated cancer now: would you allow your doctor to ignore pre-cancerous
cell changes to see if they turned into cancer?

Another
problem is cost-effectiveness.

There have
been two studies in the US,
showing that screening would be relatively cost-effective in both HIV-negative
and HIV-positive gay men. In the cost-effectiveness study in HIV-positive gay
men, the cost per quality-adjusted life-year (QALY) saved was $16,000 with
annual screening and $13,000 if done every two years.16 In
HIV-negative gay men, the cost was considerably greater if you screened annually
($34,800) but comparable if done biennially ($15,100).17

However, a UK
cost-effectiveness model found that national screening of gay men (with or
without HIV) was unlikely to be cost-effective, with an average cost per QALY
gained of £39,405, which is way beyond the usually quoted NICE (National
Institute for Health and Clinical Excellence) threshold of £30,000.18
It was actually more cost-effective to screen all gay men in this study, rather
than just the HIV-positive ones.

This model,
however, contained a number of different assumptions from the US models. In
the US,
it was assumed that annual rate of transition from high-grade AIN to anal
cancer was high: from 3.6 to 5% a year. Actual surveys suggest a lower rate of
progression. The UK
study assumed a much lower rate: about one case of anal cancer per 500 cases on
untreated AIN grades 2 or 3 (0.2%), or one case per 2500 treated cases. This is
probably on the low side, and there have been a number of other criticisms
levelled at the UK
paper, such as the assumption of a high rate of regression from AIN 1 to
asymptomatic.

Screening gay men for anal cancer
and its precursors has not been recommended in UK guidelines. The British HIV Association’s cancer
guidelines of 2008 state: “there is little evidence for routine [screening] as
the early detection of lesions still poses substantial difficulties and single
biopsies may miss areas of AIN, with histology and cytology yielding some
discordant results.”19

In complete contrast, US guidelines
– such as those from New York State20 – recommend “anal cytology at baseline and annually”, especially for men with HPV or
anal warts, and the European AIDS Clinical Society (EACS) guidelines recommend
a rectal examination and/or smear every one to three years for gay men.21
Anoscopy would be reserved for people with abnormal cytology results, and the
New York guidelines estimate that this would be less than 30% of the screened
population.

Treatment

One of the
reasons screening is not nationally adopted in the UK is because, to quote the BHIVA
guidelines, “Treatment options for AIN are limited by morbidity and high
recurrence rates.” That probably isn’t as true as it was. The becoming-standard
treatment for AIN is infrared coagulation therapy (ICT) which involves burning
off the affected areas with a heat gun. That sounds very painful, but can be
carried out under local anaesthetic, causing only a couple of days’ discomfort.
High recurrence rates are still a problem: after one treatment, 50% of
HIV-negative gay men and 65% of HIV-positive ones had recurrent lesions within
ten months. Until we get more data, we don’t know if these treatments are
preventing progression to cancer – or just subjecting people to unnecessary
discomfort.

If you are
one of the unlucky few who get anal cancer, it’s not the end of the world. With
a survival rate of 65% at five years, anal cancer looks bad compared to
testicular cancer (97% alive at five years), but very good compared to advanced
lung cancer (5% alive at five years). Surgery is not necessary for the majority
of people if anal cancer is diagnosed before it becomes invasive. The standard
treatment is radiotherapy, plus the anti-cancer drugs mitomycin C and
capecitabine, or cisplatin – the kind of drugs that are much more tolerable
these days, thanks to anti-emetic drugs.

Less easy to
get on with is the radiotherapy, which involves a daily visit to the clinic for
six weeks, and causes proctitis (anal and rectal inflammation and pain) for
another six weeks or so after that. After these treatments it’s the usual
watchful wait to see if it’s really gone or if it recurs.

About that vaccine...

What about
getting yourself vaccinated? And should we be vaccinating adolescent boys as
well as girls anyway, in case they get HPV 16 or 18?

In January
this year, the US Food and Drug Administration approved the use of Gardasil to prevent anal cancer in
people (of both sexes) between the ages of 9 and 26. So far, the European
Medicines Agency (EMA) has not followed suit. In the decentralised healthcare
system of the US,
this is by no means a guarantee that your healthcare system will agree to pay
for Gardasil, but it does mean that
people who fall within the age criteria have a fighting chance. In a system
like the UK’s NHS, EMA approval would only be the first step anyway, as
medicines then have to undergo the eagle-eye scrutiny of our health technology
assessment agency NICE, before the NHS will agree to provide it for free (and,
for reasons of cost, the NHS approved Cervarix
for vaccinating adolescent girls, not Gardasil).

The US
approval followed a study22 that found that Gardasil had 65% efficacy in preventing anal lesions caused by the
four types it immunises against in young men aged 19 to 26. That was for all
the men who entered the study – and some who were already infected with HPV 16
or 18. The efficacy in men not already infected when they entered the study was
90%.

However, this
tells us nothing about whether Gardasil
really prevents anal cancer or even AIN – because nearly all the anal lesions
seen were anal warts caused by types 6 and 11.

If you’re
older and gay, surely it’s too late to vaccinate? Well... not necessarily,
because the body can get rid of HPV infections, remember. There is very little
research in this area, but a 2009 study largely of gay, HIV-positive, male US
Army veterans found that 43% did not have antibodies to HPV types 16 or 18.23
This could mean they’d just been infected and not yet developed an antibody
response, but it could also mean they’d never been infected or had got rid of
their infection. An HPV DNA test would tell.

So might you
benefit from getting the vaccine? Only if you can find out which HPV types you
have and if you’ve never had type 16 or 18. In theory the HPV vaccine could
protect you from reinfection but we don’t know whether it actually does. The
vaccine has no effect on current infections. You’ll only get it done privately
at present and, at £480 for a three-shot course of Gardasil (Cervarix costs
about £315 privately) it is not cheap, and that’s not counting the costs of
consultation and testing.

Conclusion

So what’s a
boy to do who is worried about HPV and anal cancer, possibly because he’s had
anal warts? “You should get screened annually and if you’re diagnosed with any
lesions, you should ask for a referral to a specialist centre like ours,” is
Mark Bower’s conclusion. The same would also apply if you are an HIV-positive
woman who has anal sex. There’s an inevitable contradiction here: while UK
cost-effectiveness modellers still come out against anal screening as standard
for people with HIV, on an individual level, it is wise to talk to your doctor
about getting yourself checked out with a smear test.

You may also
want to do a regular self-examination of your anus, although in most cases the
lesions caused by high-risk HPV strains tend to be flat and you won’t be able
to feel anything. But if you do feel anything lumpy, you should certainly have
it seen by a doctor as soon as possible. Other symptoms to report promptly are
abnormal discharge or bleeding from the anus, itching, pain or pressure around
the anus, and anal sores that do not heal. (These symptoms can also be caused
by other, more common, problems.)

In a world
where HIV therapy is relatively standardised, the mess of contradictory
evidence and recommendations around anal cancer thrusts us back to the time
when HIV treatment itself was experimental and controversial, and you had to
hunt for a hospital that agreed that viral load tests were cost-effective.
Keeping yourself safe from anal cancer is one area where patient power makes a
difference, and it pays to demand the best service. Get your rear end checked
out regularly, and don’t die of embarrassment.

de Pokomandy A et al. HAART and progression to high-grade anal
intraepithelial neoplasia in men who have sex with men and are infected with
HIV. Clin Infect Dis, online edition, doi: 10.1093/cid/cir064, 2011.

Berman S et al. Seroprevalence of
antibodies to HPV-16 and HPV-18, and correlation with the presence of HPV DNA
and anorectal cytologic abnormalities in a cohort of HIV-positive men involved
in a study of HIV-positive males receiving the quadrivalent HPV vaccine,
Gardasil. 5th IAS Conference on HIV Treatment, Pathogenesis and
Prevention, Cape Town,
abstract WeB102, 2009.

Issue 208: July 2011

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.